Disulfiram Attenuates Acinetobacter baumannii-Induced Hyperinflammation by Regulating Inflammatory Pathways: Insights...

The emergence of carbapenem-resistant Acinetobacter baumannii (CRAB) poses a major obstacle in treating sepsis, highlighting the urgent need for new therapeutic approaches. Recent studies have reported that disulfiram (DSF) exhibits antibacterial activity and potentiates meropenem activity against resistant A. baumannii (A. baumannii) isolates. The mechanisms by which DSF modulates inflammation during A. baumannii infection remain unclear, although DSF possesses anti-inflammatory properties by regulating the pyroptosis pathway. The present study aimed to investigate the potential effect of DSF in modulating inflammatory responses during CRAB infection. We observed DSF treatment in A. baumannii-infected cells resulted in inhibiting NF-κB activity and NLRP3 inflammasome formation, which decreases expression and secretion of IL-1β, IL-6, and TNF-α in human THP-1 cell-derived macrophages. Further, RNA sequencing was performed to determine how DSF suppresses the CRAB-associated inflammation. The transcriptomic data analysis revealed downregulation of genes involved in inflammatory pathways, including the NF-κB signaling pathway, toll-like receptor signaling pathway, and cytokine-cytokine receptor interaction pathway, in DSF-treated cells, which indicates its anti-inflammatory effects in suppressing A. baumannii-induced inflammation. Collectively, our findings demonstrate that DSF is a promising candidate for modulating inflammatory responses during CRAB infection; however, further validation through in vivo and clinical studies is necessary.